We analyzed usable data from all randomized controlled studies examining any TAAR1 agonist in comparison to placebo or current antipsychotics in people with psychosis, other mental health conditions, or healthy volunteers.
We examined efficacy outcomes, including overall symptoms of psychosis (primary) and symptom domains, dropouts due to any reason, and adverse events. Safety outcomes included death, serious adverse events, and specific adverse events. We also sought mechanistic outcomes, specifically neurobiological measures of dopaminergic, glutamatergic, and serotonergic signaling. We examined these outcomes at three time points: immediately after a single dose up to 2 weeks of treatment, 3-13 weeks of treatment (preferably at 6 weeks), and longer-term outcomes.
In terms of efficacy outcomes, we pooled the data for each specific subgroup, considering that differences can be expected among different diagnoses (e.g., schizophrenia and Parkinson’s disease psychosis) and patient subgroups (e.g., patients with an acute episode of schizophrenia or with predominant negative symptoms). In terms of other outcomes, we combined data from all subgroups but also presented data separately for each subgroup.
Summary of data extraction: For continuous outcomes, we preferred change over endpoint scores and data from appropriate models or imputations considering missing outcome data. For dichotomous outcomes, we again preferred data from all participants, but in case of participants with missing outcome data, we assumed that they did not experience the event; an assumption usually used in meta-analysis in schizophrenia (e.g., Huhn et al. 2023). In terms of crossover studies, we preferred data from appropriate models considering period or carry-over effects. If not available, we assumed a correlation (i.e., 0.2 for adverse events) to correct the variance of the estimates according to Elbourne et al. 2002. If an outcome was measured multiple times after a single dose of the drug, we calculated the area under the curve according to the linear trapezoid rule (Chiou et al. 1978) and divided by the time of assessment to remove the time component.
Risk of bias was assessed using the RoB2 tool for parallel and crossover studies. When only one domain had some concerns, we assigned an overall low risk of bias. Otherwise, we used the worst judgment across domains.
The effect sizes were as follows: 1) standardized mean differences (SMD) for efficacy outcomes, given that various scales have been used in the literature to allow comparability of the findings with other studies of antipsychotic drugs; 2) mean differences (MD) for laboratory measures, i.e., weight (kg), QTc interval (msec), and prolactin levels (ng/ml); 3) odds ratios (OR) for dichotomous outcomes, which were also converted to absolute risks using a control event rate (see 7. for meta-analysis). 95% confidence intervals (95% CI) are presented, but 95% prediction intervals are not presented due to the small number of studies. Other effect sizes were not used in the first iteration of the review, e.g., those used in meta-analysis of variance due to the paucity of data.
Meta-analysis was conducted primarily using a random-effects model with inverse variance and REML estimator of tau-squared. Due to the small number of studies (<5) in all analyses, we corrected the confidence intervals using the Hartung-Knapp method, and we also presented the findings from fixed-effects models using the Mantel-Haenszel method throughout. Meta-analysis of proportions was conducted to pool the control groups to estimate the control event rate using logit transformation of the proportions and inverse variance method. Moreover, continuity corrections of 0.5 were applied in case of 0 events in one of the groups.
Sensitivity analysis of the primary outcome included using fixed-effect methods (post-hoc due to the small number of studies), restricting the analysis to studies with an overall low risk of bias, and excluding studies with imputed values.
Subgroup analyses and meta-regressions were not conducted due to the paucity of data. However, we explored potential dose-effects for the primary outcome by plotting the effect sizes for different fixed doses of TAAR1 agonists compared to placebo (while correcting for the use of common comparators).
Summary of evidence tables were constructed for all outcomes, including a summary of the association, biases due to study limitations, biases due to reporting bias, biases due to indirectness, and other biases. We adapted the GRADE approach. We used the ROB-ME approach for evaluating biases in missing evidence for the primary outcomes and considered the percentage of missing studies and participants for secondary outcomes. Indirectness was considered especially relevant for non-efficacy outcomes, where we pooled data across diagnoses and subgroups, and considered the percentage of studies and participants with schizophrenia, the main group for which this evidence would be applicable.
Please see the manuscript and the protocol for more details.
We present below the results, including the PRISMA flow diagram, table of included studies, risk of bias assessment, and forest plots, to facilitate a better understanding of the summary of evidence tables and the manuscript. Please refer to the detailed description of the findings in the latter part of the manuscript for more information.
Figure 1 PRISMA 2020 flow diagram
| Name | Title | ID | Sponsor | Design | Population | Intervention | Sample size | Objectives | Start date | Completion date | Completion year | Status | Available data |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DA801002 (in Galluppi 2021) | Population pharmacokinetic analysis of ulotaront in subjects with schizophrenia | DA801002 | Sunovion/Sumitomo | SB-RCT single ascending dose (phase I) | Men >18 years | Ulotaront (25mg to 50mg); Placebo | 16 | Pharmacokinetics | NA | NA | 2021 | completed | None |
| Fowler (2015) | A UGT2B10 Splicing Polymorphism Common in African Populations May Greatly Increase Drug Exposure | NA | Hoffmann-La Roche | DB-RCT; single ascending dose (phase I) | Men 18-45 years | RO5263397 (1mg to 125mg); Placebo | 49 | Tolerability, pharmacokinetics | NA | NA | 2015 | completed | None |
| Hopkins (2021) | Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans | SEP361-103 | Sunovion/Sumitomo | DB-RCT two-period crossover; single dose (phase I) | Men 18-35 years | Cohort 1: Ulotaront 10mg; Placebo; Cohort 2: Ulotaront 50mg; Placebo | 24 | Sleep parameters, pharmacokinetics | NA | NA | 2021 | completed | Dropouts, side-effects |
| Isaacson (2023) | Ulotaront, a Trace Amine-Associated Receptor 1/Serotonin 5-HT1A Agonist, in Patients With Parkinson Disease Psychosis: A Pilot Study. | SEP361-203, NCT02969369 | Sunovion/Sumitomo | DB-RCT; 6 weeks (with open label extension) (phase 2) | Men/women ≥55 years with Parkinson’s disease psychosis (acute) | Ulotaront 20-75mg/d; Placebo | 39 | Efficacy (acute), safety | 21.11.16 | 05.07.23 | 2023 | completed | Efficacy, dropouts, side-effects |
| JapicCTI-194581 (2019) | A Phase I Single-Ascending Dose and Multiple-Ascending Dose Study of RO6889450 in Healthy Japanese Male | JapicCTI-194581 | Hoffmann-La Roche | DB-RCT; single and multiple ascending dose (phase I) | Men 20-45 years | Ralmitaront; Placebo | 64 | Tolerability, pharmacokinetics | 27.01.19 | 23.10.19 | 2019 | completed | None |
| Koblan (2016) | A phase 1 open label safety and tolerability study of SEP-363856, a novel NON-D2 mechanism of action molecule, in patients with schizophrenia | SEP361-106, NCT01994473 | Sunovion/Sumitomo | SB-RCT; multiple ascending dose for 1 week (including open label extension) (phase 1) | Men/women 18-55 years with schizophrenia (stable, DSM-IV-TR) | Ulotaront (10mg/d to 100mg/d); Placebo | 48 | Tolerability, pharmacokinetics | 41334 | 41974 | 2014 | completed | None |
| Koblan (2020) | A Non–D2-Receptor-Binding Drug for the Treatment of Schizophrenia | SEP361-201, NCT02969382, EUCTR2016-001555-41 | Sunovion/Sumitomo | DB-RCT; 4 weeks (with open label extension) (phase 2) | Men/women 18-40 years with schizophrenia (acute, DSM-5) | Ulotaront (50-75mg/d); Placebo | 245 | Efficacy (acute), tolerability | 05.12.16 | 31.07.18 | 2018 | completed | Efficacy, dropouts, side-effects |
| NCT01940159 (2013) | A Study Assessing the Safety, Tolerability, and Pharmacokinetics of SEP-363856 in Male and Female Subjects With Schizophrenia | SEP361-105, NCT01940159 | Sunovion/Sumitomo | SB-RCT; single ascending dose (phase 1) | Men/women 18-50 years with schizophrenia (stable, DSM-IV-TR) | Ulotaront (50mg to 150mg); Placebo | 48 | Tolerability, pharmacokinetics | 41334 | 41730 | 2014 | completed | None |
| NCT02699372 (2016) | The Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of RO6889450 in Healthy Volunteers | BP30134, NCT02699372 | Hoffmann-La Roche | DB-RCT; single and multiple ascending dose up to 2 weeks (phase I) | Men/women 18-45 years | Ralmitaront (5 mg to 450mg); Placebo | 164 | Tolerability, pharmacokinetics | 21.03.16 | 14.04.17 | 2017 | completed | None |
| NCT03669640 (2018) | A Study to Assess the Effects of RO6889450 (Ralmitaront) in Participants With Schizophrenia or Schizoaffective Disorder and Negative Symptoms | BP40283, NCT03669640, EUCTR2020-004752-16, JPRN-jRCT2031200287 | Hoffmann-La Roche | DB-RCT; 12 weeks (phase II) | Men/women 18-55 years with schizophrenia or schizoaffective (predominant negative symptoms, DSM-5) | Part A: Ralmitaront; placebo (monotherapy); Part B: Ralmitaront low or high dose; placebo (add-on to current antipsychotics) | 128 | Efficacy (negative symptoms), tolerability | 04.12.18 | 08.05.23 | 2023 | completed | None |
| NCT04072354 (2019) | A Clinical Trial to Study the Efficacy and Safety of an Investigational Drug in Acutely Psychotic People With Schizophrenia | SEP361-301, NCT04072354, EUCTR2019-000470-36 | Sunovion/Sumitomo | DB-RCT; 6 weeks (phase 3) | Men/women 13-17 and 18-65 years with schizophrenia (acute, DSM-5) | Ulotaront 50mg/d; Ulotaront 75mg/d; Placebo | 463 | Efficacy (acute), tolerability | 11.09.19 | 08.06.23 | 2023 | completed | Efficacy, dropouts |
| NCT04092686 (2019) | A Clinical Trial That Will Study the Efficacy and Safety of an Investigational Drug in Acutely Psychotic People With Schizophrenia | SEP361-302, NCT04092686, EUCTR2019-000697-37 | Sunovion/Sumitomo | DB-RCT; 6 weeks (phase 3) | Men/women 18-65 years with schizophrenia (acute, DSM-5) | Ulotaront 75mg/d; Ulotaront 100mg/d; Placebo | 462 | Efficacy (acute), tolerability | 30.09.19 | 08.09.23 | 2023 | completed | Efficacy, dropouts |
| NCT04115319 (2019) | A Study of the Long-term Safety and Tolerability of an Investigational Drug in People With Schizophrenia. | SEP361-304, NCT04115319 , EUCTR2019-002259-40 | Sunovion/Sumitomo | DB-RCT; 52 weeks (phase 3) | Men/women 18-65 years with schizophrenia (stable, DSM-5) | Ulotaront 50-100mg/d; Quetiapine XR 400-800mg/d | 475 | Efficacy (maintenance), tolerability | 15.11.19 | 30.12.22 | 2022 | completed | None |
| NCT04325737 (2020) | Study Assessing the Safety, Tolerability, and Pharmacokinetics of SEP-363856 in Japanese Male and Female Subjects With Schizophrenia | DA801102, NCT04325737, jRCT2080225100 | Sunovion/Sumitomo | DB-RCT; 2 weeks (phase 1) | Men/women 18-65 years with schizophrenia (stable, DSM-5) | Cohort 1: Ulotaront (50mg/d to 100mg/d); Placebo; Cohort 2: Ulotaront (25mg/d to 100mg/d); Placebo | 13 | Tolerability, pharmacokinetics | 31.03.20 | 07.08.20 | 2020 | completed | None |
| NCT04512066 (2020) | A Trial of the Efficacy and the Safety of RO6889450 (Ralmitaront) vs Placebo in Patients With an Acute Exacerbation of Schizophrenia or Schizoaffective Disorder | BP41743, NCT04512066, JPRN-jRCT2031200288 | Hoffmann-La Roche | DB-RCT; 8 weeks (up to 48 weeks extension) (phase II) | Men/women 18-45 years with schizophrenia or schizoaffective disorder (acute, DSM-5) | Ralmitaront 45mg/d; Ralmitaront 150mg/d; Risperidone 4mg/d; Placebo | 287 | Efficacy (acute), tolerability | 08.09.20 | 21.06.22 | 2022 | completed | Efficacy, dropouts, side-effects |
| NCT04825860 (2021) | A Clinical Trial to Evaluate the Efficacy and Safety of SEP-363856 in Acutely Psychotic People With Schizophrenia, Followed by an Open-label Extension Phase | DA801201, NCT04825860, jRCT2071210003 | Sunovion/Sumitomo | DB-RCT; 6 weeks (and open label extension) (phase 2/3) | Men/women 18-65 years with schizophrenia (acute, DSM-5) | Ulotaront 50mg/d; Ulotaront 75mg/d; Placebo | 480 | Efficacy (acute), tolerability | 29.03.21 | 30.06.25 | NA | ongoing | None |
| NCT05402111 (2022) | A Clinical Study That Will Assess How Food Moves Through the Stomach and Effects Blood Glucose Levels in Subjects With Schizophrenia Taking SEP-363856 or and Prior Antipsychotic (PA) Standard | SEP361-124, NCT05402111 (2022) | Sunovion/Sumitomo | Open RCT two-period crossover; single dose (phase 1) | Men/women 18-65 years with schizophrenia (stable, DSM-5) | Ulotaront (25mg to 50mg); Prior antipsychotics (risperidone, olanzapine, quetiapine, aripiprazole) | 36 | Pharmacokinetics, metabolic parameters | 13.06.22 | 13.07.23 | NA | ongoing | None |
| NCT05542264 (2022) | A Clinical Study That Will Assess the Effect of SEP-363856 or Prior Antipsychotic (PA) Standard of Care on Body-weight Associated Parameters in Subjects With Schizophrenia | SEP361-122, NCT05542264 | Sunovion/Sumitomo | DB-RCT; 2 weeks (phase 1) | Men/women 18-65 years with schizophrenia (stable, DSM-5) | Ulotaront; Prior antipsychotics (risperidone, olanzapine, quetiapine, aripiprazole) | 60 | Metabolic parameters | 15.11.22 | 23.10.23 | NA | ongoing | None |
| NCT05593029 (2022) | A Trial of the Safety and Efficacy of SEP-363856 in the Treatment of Adults With Major Depressive Disorder | 382-201-00001, NCT05593029 | Sunovion/Sumitomo | DB-RCT; 14 weeks (phase 2/3) | Men/women 18-65 years with MDD (acute, DSM-5) | Ulotaront; Placebo (add-on to antidepressants) | 900 | Efficacy (MDD), tolerability | 09.11.22 | 45778 | NA | ongoing | None |
| NCT05729373 (2023) | A Clinical Study That Will Meaure How Well SEP-363856 Works and How Safe it is in Adults With Generalized Anixety Disorder | SEP361-226, NCT05729373, EUCTR2022-502077-42-00 | Sunovion/Sumitomo | DB-RCT; 8 weeks (phase 2/3) | Men/women 18-65 years with GAD (acute, DSM-5) | Ulotaront (50-75mg/d); Placebo | 464 | Efficacy (GAD), tolerability | 08.03.23 | 08.02.25 | NA | ongoing | None |
| NCT05848700 (2023) | A Clinical Study to Learn if SEP-363856 Has Physical Dependence in Adults With Schizophrenia | SEP361-121, NCT05848700 | Sunovion/Sumitomo | DB-RCT; 10 weeks (phase 1) | Men/women 18-65 years with schizophrenia (stable, DSM-5) | Ulotaront continuation; Ulotaront discontinuation (switch to placebo) | 60 | Physical dependence, pharmacokinetics | 21.06.23 | 23.02.24 | NA | ongoing | None |
| Perini (2023) | Effects of ulotaront on brain circuits of reward, working memory, and emotion processing in healthy volunteers with high or low schizotypy | SEP361-104, NCT01972711 | Sunovion/Sumitomo | DB-RCT; single dose (phase 1) | Men/women 18-45 years (high or low levels of schizotypy) | Ulotaront 50mg; Amisulpride 400mg; Placebo | 105 | fMRI | 41699 | 42186 | 2015 | completed | Dropouts, side-effects |
| SEP361-101 (in Galluppi 2021 and Chen 2022) | A sensitive LC-MS/MS method for simultaneous quantification of ulotaront and its N-desmethyl metabolite in human plasma and application to a clinical study | SEP361-101 | Sunovion/Sumitomo | SB-RCT; single ascending dose (phase I) | Men >18 years | Ulotaront (5mg to 125mg); Placebo | 52 | Pharmacokinetics | NA | NA | 2021 | completed | None |
| Szabo (2023) | A multicenter, double-blind, placebo-controlled, randomized, Phase 1b crossover trial comparing two doses of ulotaront with placebo in the treatment of narcolepsy-cataplexy. | SEP361-108 , NCT05015673 | Sunovion/Sumitomo | DB-RCT three-period crossover; 2 weeks (phase 1) | Men/women 18-55 years with narcolepsy/cataplexy | Ulotaront 25mg; Ulotaront 50mg; Placebo | 18 | Sleep parameters, pharmacokinetics, tolerability | 05.06.14 | 26.05.15 | 2015 | completed | Dropouts, side-effects |
| Tsukada (2023) | A randomized, single-dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia. | SEP361-114, NCT04369391 | Sunovion/Sumitomo | DB-RCT three-period crossover; single dose (phase 1) | Men/women 18-65 years with schizophrenia (stable, DSM-5) | Ulotaront 150mg; Placebo; Moxifloxacin 400mg (ineligible for the review) | 68 | QTc interval, tolerability, pharmacokinetics | 18.06.20 | 10.11.20 | 2020 | completed | Dropouts, side-effects |
Table 1 Table of included studies.
There were 25 eligible studies, which characteristics can be found in Table 1, with 20 studies (2147 participants) being completed and 5 studies being still ongoing up to 20.01.2024. There were usable data for this analysis from 9 studies (1711 participants), which enrolled adult populations across multiple countries and were funded by the industry manufactuing the TAAR1 agonists.
The usable studies compared single or multiple doses of two TAAR1 agonists (i.e., ulotaront or ralmitaront) with placebo or current antipsychotics (i.e., risperidone or amisulpride) in people with schizophrenia, Parkinson’s disease psyschosis, other mental health conditions (narcolepsy/cateplexy as sleep disorder) and healthy volunteers. Five studies used a parallel design to examine the efficacy and safety of multiple doses of TAAR1 agonists in psychosis within 3-13 weeks Four studies examining daily doses of TAAR1 agonists in adults with an acute episode of schizophrenia spectrum conditions for 4-6 weeks, 3 examined ulotaront (Koblan et al. 2020, NCT04072354 and NCT04092686) and 1 examined ralmitaront (NCT04512066). These studies used placebo as control group, and the 1 study on ralmitaront used also the antipsychotic risperidone as active comparator. One study comparing daily doses of ulotaront in Parkinson’s dissease psychosis to placebo for 4 weeks (Isaacson et al. 2023). Four studies examined the pharmacokinetics, safety and/or neuroimaging of single doses of TAAR1 agonists or multiple doses for up to 2 weeks: One study examining the effects of a single dose of 150mg ulotaront in *clinically stable adults with schizophrenia** on QTc interval within a day (Tsukada et al 2023). The study utilized a three-period crossover period comparing ulotaront with placebo and moxifloxacin (an antibiotic used as active comparator, not relevant for our analysis). Two studies examined the effects of single doses of ulotaront in healthy volunteers on sleep parameters (Hopkins et al 2021) or fMRI tasks (Perini et al 2023). Hopkins et al 2021 included two cohorts of crossover studies comparing two single doses of ulotaront with placebo. Perini et al 2023 was a parallel trial comparing ulotaront to placebo or the antipsychotic amisulpride on fMRI tasks relevant to reward, working memory and emotion processing in volunteers with high or low schizotypy traits. One study examined two single doses of ulotaront in adults with narcolepsy-cateplyxy compared to placebo using a three-period crossover design.
The following studies were unavailable: One study examined the efficacy and safety of ulotaront in comparison to placebo in adolescents with an acute episode schizophrenia (NCT04072354). This study had two parts with adults and adolescents. This study has been recently completed, and although some usable data in the adult population are available (see above), these are not available for the adolsecents. One study examined the long-term efficacy and safety of ulotaront in comparisong to the antispychotic quetiapine in adults with clinically stable schizophrenia (NCT04115319). The study should have been completed in 12.2022, and there are currently no usable data available. One study examined monotherapy or add-on treamtent with ralmitaront in comparison to placebo in adults with schizophrenia or schizoaffective disorder and predominant negative symptoms (NCT03669640). The study has been recently completed in 05.2023, and it has been reported to be failed, yet no usable data were available. Nine studies examined pharmacokinetics and safety of single or few multiple doses of ulotaront or ralmitaront in healthy volunteers (Fowler 2015, JapicCTI-194581, NCT02699372, SEP361-101, DA801002, NCT01940159, Koblan 2016, NCT04325737, NCT04865835).
The following studies are ongoing: - One study is examining the efficacy and safety of two ulotaront doses of 50mg/d and 75mg/d in comparison to placebo in adults with an acute episode of schizophrenia (NCT04825860). The study is expected to be completed in 06.2025. - Two studies are examining the efficacy and safety of ulotaront compared to placebo in other mental health conditions, i.e., adults with major depression (NCT05593029) and generalized anxiety disorder (NCT05729373). These trials are expected to be completed in 2025, and their safety data are relevant for this review.
The risk of bias of the studies was examined using the RoB2 tool for parallel and crossover studies for all outcomes. Here, we present the risk of bias of using the worst judgement of a domain across outcomes. It should be noted that when there were some concerns in only one of the domains, we assigned an overall low risk of bias according to our protocol.
Figure 2 Risk of bias of studies with usable data
All the studies were double-blind randomized controlled studies, with a low risk of bias in most cases in their respective domains of biases due to randomization, deviations from intended interventions, and outcome measurement. There were also no indications of selectively reported results; thus, the studies had a low risk of bias in their respective domains. Most of the studies had missing outcome data, but there was no clear indication that the missingness depended on the true value of the effects for most of the outcomes. Therefore, there were some concerns, except for Isaacson et al. 2023, which had a high risk of bias for efficacy outcomes but not for adverse events and other outcomes. Additionally, there were few differences in this domain across outcomes, such as a low risk for the outcome of dropouts. In terms of the three crossover studies, there was a low risk of bias in period and carry-over effects, except for some concerns in the three-period crossover study of Tsukada et al. 2023. Few differences across outcomes can be found in the overall judgment of the risk of bias for each study per outcome in the respective forest plots below.
No usable data available from RCT.
Figure 3 Forest plot for overall symptoms (primary outcome) for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)
No usable data available from RCT.
No usable data available from RCT.
Figure 4 Forest plot for positive symptoms for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)
No usable data available from RCT.
No usable data available from RCT.
Figure 5 Forest plot for negative symptoms for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)
No usable data available from RCT.
No usable data available from RCT.
Figure 6 Forest plot for depressive symptoms for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)
No usable data available from RCT.
No usable data available from RCT.
Figure 7 Forest plot for cognitive impairment (measured with MMSE) for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
Figure 8 Forest plot for response (>50% or 20% symptom reduction from baseline) for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
Figure 9 Summary plot for efficacy outcomes at 4-6
weeks for the comparison of TAAR1 agonists vs. placebo in the two
populations of patients with an acute episode of schizophrenia and
Parkinson’s disease psychosis. There were only available data for the
timepoint of 3-13 weeks. The size of the points are proportional to the
number of participants used in the analysis. SMD>0 correspond to more
symptom improvement by TAAR1 agonists compared to placebo.
Figure 10 Forest plot for dropouts due to any reason
for the comparison of TAAR1 agonist vs. placebo at 1 day - 2
weeks.Studies with no estimable effect size had 0 events in both
arms.
Figure 11 Forest plot for dropouts due to any reason
for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary
timepoint)
No usable data available from RCT.
Figure 12 Forest plot for dropouts due to adverse event for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks. Studies with no estimable effect size had 0 events in both arms.
Figure 13 Forest plot for dropouts due to adverse event for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)
No usable data available from RCT.
Figure 14 Forest plot for serious adverse events for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks. Studies with no estimable effect size had 0 events in both arms.
Figure 15 Forest plot for serious adverse events for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint)
No usable data available from RCT.
There were available usable data from four studies (i.e., Hopkins et al 2021, Perini et al 2023, Szabo et al 2023 and Tsukada et al 2023) but all of them reported 0 deaths so that could not provide estimable effect sizes with the current approach.
Figure 16 Forest plot for death for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). Studies with 0 events in both arms could not provide estimable effect sizes with the current approach.
No usable data available from RCT.
Figure 17 Forest plot for any adverse events for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks.
Figure 18 Forest plot for any adverse event for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).
No usable data available from RCT.
Figure 19 Forest plot for anticholinergic side-effects (i.e., dry mouth) for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks.
No usable data available from RCT.
No usable data available from RCT.
Terms that were considered as reported in the trials: hypotension or orthostatic hypotension
No usable data available from RCT.
Figure 20 Forest plot for hypotension for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).
No usable data available from RCT.
Figure 21 Forest plot for dizziness for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks.
Figure 22 Forest plot for dizziness for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).
No usable data available from RCT.
Figure 23 Forest plot for nausea or vomiting for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks.
Figure 24 Forest plot for nausea or vomitting for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).
It should be noted that there appears to be some heterogeneity in the findings between ulotaront and ralmitaront. This heterogeneity may potentially be driven by the fact that ulotaront is also a 5-HT1A receptor partial agonist, which is associated with gastrointestinal symptoms.
No usable data available from RCT.
Terms that were considered as reported in the trials: QTc prolongation above ≥450 msec or an increase of ≥60 msec (any threshold was eligible)
Figure 25 Forest plot for QTc prolongation for the
comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks. Studies with
not estimable effect sizes had 0 events in both groups.
There were available data in Koblan et al 2020, which reported 0 events in both groups, so that an effect. size cannot be estimated with the current approach.
No usable data available from RCT.
Figure 26 Forest plot for QTc interval in msec for the comparison of TAAR1 agonist vs. placebo at 1 day - 2 weeks.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
Figure 27 Forest plot for weight gain for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).
No usable data available from RCT.
No usable data available from RCT.
Figure 28 Forest plot for weight change in kg for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).
No usable data available from RCT.
There were available data from one study Hopkins et al 2021 reporting 0 events in both arms so that an effect size cannot be estimated with the current approach.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
Figure 29 Forest plot for prolactin levels in ng/ml for
the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary
timepoint). SD was imputed from the dataset of antipsychotic trials in
Huhn et al 2021.
No usable data available from RCT.
Terms considered included: restlessness (when was used to describe akathisia)
No usable data available from RCT.
Figure 30 Forest plot for akathisia for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).
No usable data available from RCT.
No usable data available from RCT.
Figure 31 Forest plot for extrapyrmidal side-effects
(use of antiparkinsonian medication as proxy) for the comparison of
TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). No data
were available from the two unpublished ulotaront trials (i.e.,
NCT04072354, NCT04092686), the study on Parkinson disease psychosis
(Isaacson 2023), and the unpublisshed study on ralmitaront
(NCT04512066).
Furthermore, data presented in a conference abstract at the ACNP 2023 regarding NCT04072354 and NCT04092686 describe that ulotaront did not differ in experimental side-effect compared to placebo.
No usable data available from RCT.
There were usable data for one study Perini et al 2023, which reported 0 events in both groups so that an effect size could not be estimated with the current approach.
Figure 32 Forest plot for anxiety as adverse event for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).
No usable data available from RCT.
No usable data available from RCT.
Figure 33 Forest plot for agitation for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).
No usable data available from RCT.
Figure 34 Forest plot for headache for the comparison of TAAR1 agonist vs. placebo at 1 day to 2 weeks.
Figure 35 Forest plot for headache for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).
No usable data available from RCT.
Terms that were considered as reported in the trials: fatigue, sedation, somnolence
Figure 36 Forest plot for sedation for the comparison of TAAR1 agonist vs. placebo at 1 day to 2 weeks.
Figure 37 Forest plot for sedation for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint).
No usable data available from RCT.
No usable data available from RCT.
Figure 38 Forest plot for insomnia for the comparison of TAAR1 agonist vs. placebo at 3-13 weeks (primary timepoint). Potential differences between ulotaront and ralmitaront could be explained by their differnet pharmacological profile.
No usable data available from RCT.
Figure 39 Summary forest plot for dropouts and
side-effects for the comparison of TAAR1 agonists compared to placebo
and for the two timepoints with usable data. It should be noted that
different populations have been pooled in the analysis of dropouts and
adverse events including schizophrenia, Parkinson’s disease psychosis,
narcolepsy-cateplexy and healthy volunteers. The size is proportional to
the number of participants in the analysis. OR>1 corresponds to more
events with TAAR1 agonists compared to placebo.
No usable data were available from RCTs. However, Perini et al. 2023 examined the effects of single doses of ulotaront compared to placebo in volunteers with low or high schizotypy traits on fMRI of BOLD responses to neuropsychological tasks that could be considered only as weak proxies for neurotransmitter signaling. Thus, they were not quantitatively further analyzed but narratively described in this iteration of the review. The primary outocme of this study was the response of the changes in BOLD responses in the striatum during the anticipation phase of the monetary incentive delay (MID) task and interaction with schizotypy traits. This was potentially selected a posteriori given that the complete protocol was not available and the
Specifically, ulotaront, compared to placebo, appeared to reverse increased BOLD responses in the striatum during the anticipation phase of the monetary incentive delay (MID) task in participants with high schizotypy traits compared to those with low schizotypy traits. This was the primary outcome of this study, which selection was described to be due to its relevance to reward processing and increased dopamine synthesis capacity, thus serving as a weak proxy for ulotaront’s effects on decreasing presynaptic dopamine synthesis capacity. However, there is possibility that this outcome was selected a posteriori due to significant findings and the protocol of the study was not available and the clinicaltrials.gov did not specify a primary outcome. Thus, there is the possibility of risk of bias of selected reported outcome. There were also differences between ulotaront and placebo in some other fMRI and neuropsychological measures, including that ulotaront compared to placebo decreasing the performance in N-back tasks (working memory measure) and emotional test battery ().
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
Figure 40 Forest plot for overall symptoms (primary
outcome) for the comparison of TAAR1 agonist vs. antipsychotics at 3-13
weeks (primary timepoint)
No usable data available from RCT.
No usable data available from RCT.
Figure 41 Forest plot for positive symptoms for the
comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary
timepoint)
No usable data available from RCT.
No usable data available from RCT.
Figure 42 Forest plot for negative symptoms for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint)
No usable data available from RCT.
No usable data available from RCT.
Figure 43 Forest plot for depression symptoms for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint)
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
Figure 44 Forest plot for response to treatment
(>50% symptom reduction from baseline) for the comparison of TAAR1
agonist vs. antipsychotics at 3-13 weeks (primary timepoint)
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
Figure 45 Summary plot for efficacy outcomes at 4 weeks
for the comparison of TAAR1 agonists versus antipscyhotcs in patients
with an acute episode of schizophrenia. There were only data for the
timepoint of 3-13 weeks. SMD>0 correspond to more symptom improvement
by TAAR1 agonists compared to placebo.
Figure 46 Forest plot for dropouts due to any reason
for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2
weeks.
Figure 47 Forest plot for dropouts due to any reason
for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks
(primary timepoint).
No usable data available from RCT.
There were usable data in Perini et al 2023, whcih reported 0 events in both groups and an effect size cannot be estimated with the current approach.
Figure 48 Forest plot for dropouts due to adverse
events for the comparison of TAAR1 agonist vs. antipsychotics at 3-13
weeks (primary timepoint).
No usable data available from RCT.
Figure 49 Forest plot for serious adverse events for
the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2
weeks.
Figure 50 Forest plot for serious adverse events for
the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks
(primary timepoint).
No usable data available from RCT.
There were usable data in Perini et al 2023, whcih reported 0 events in both groups and an effect size cannot be estimated with the current approach.
There were usable data in NCT04512066, whcih reported 0 events in both groups and an effect size cannot be estimated with the current approach.
No usable data available from RCT.
Figure 51 Forest plot for any adverse event for the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks.
Figure 52 Forest plot for any adverse event for the
comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary
timepoint).
No usable data available from RCT.
Terms that were considered as reported in the trials: dry mouth (no other relevant anticholinergic side-effects were reported such as urinary retention, constipation, mydriasis or blurred vision)
Figure 53 Forest plot for anticholinergic side effects
(e.g., dry mouth in this study) for the comparison of TAAR1 agonist
vs. antipsychotics at 1 day to 2 weeks.
No usable data available from RCT.
No usable data available from RCT.
Terms that were considered as reported in the trials: hypotension or orthostatic hypotension
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
Figure 54 Forest plot for dizziness for the comparison
of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks.
No usable data available from RCT.
No usable data available from RCT.
Terms that were considered as reported in the trials: nausea, vomiting, emesis
Figure 55 Forest plot for nausea or vomitting for the
comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks.It
should be noted that the study Perini et al 2023 examined ulotaront that
is also a partial agonsit of 5-HT1A causing potentially gastrointestinal
side-effects. In comparison, ralmitaront is not a partial agonist of the
5-HT1A receptor.
Figure 56 Forest plot for nausea or vomitting for the
comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary
timepoint). It should be noted that the study NCT04512066 examined
ralmitaront, which compared to ulotaront is not a partial agonist of the
5-HT1A receptor that can be associated with gastrointestinal side
effects.
No usable data available from RCT.
Terms that were considered as reported in the trials: QTc prolongation above ≥450 msec or an increase of ≥60 msec (any threshold was eligible)
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
Terms considered included: any weight increase, weight increase >7%
No usable data available from RCT.
Figure 57 Forest plot for weight increase for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint).
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
Figure 58 Forest plot for anxiety as adverse event for
the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2
weeks.
Figure 59 Forest plot for anxiety as adverse event for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint).
No usable data available from RCT.
No usable data available from RCT.
Figure 60 Forest plot for agitation for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint).
No usable data available from RCT.
Figure 61 Forest plot for headache as adverse event for
the comparison of TAAR1 agonist vs. antipsychotics at 1 day to 2
weeks.
Figure 62 Forest plot for headache for the comparison of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary timepoint).
No usable data available from RCT.
Terms that were considered as reported in the trials: fatigue, sedation, somnolence
Figure 63 Forest plot for sedation for the comparison
of TAAR1 agonist vs. antipsychotics at 1 day to 2 weeks.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
Figure 64 Forest plot for insomnia for the comparison
of TAAR1 agonist vs. antipsychotics at 3-13 weeks (primary
timepoint).
No usable data available from RCT.
Figure 65 Summary forest plot for dropouts and
side-effects for the comparison of TAAR1 agonists compared to
antipsychotics and for the two timepoints with usable data. There were
data for single doses of ralmitaront versus amisulpride in healthy
volunteers at 1 day, and ulotaront versus risperidone in acute
schizophrenia or schizoaffective disorder at 4 weeks. The size of the
points is proporitonal tothe number of participants. OR>1 corresponds
to more events with TAAR1 agonists compared to placebo.
No usable data available from RCT.
No usable data available from RCT.
No usable data available from RCT.
There were less than 5 studies available for the analyses of the primary outcome, precluding the exploration of potential reasons of heterogeneity with subgroup analyses and meta-regressions.
Nevertheless, we explored potential differences between ulotaront and ralmitaront in improving overall symptoms of acute schizophrenia, and potential dose-effects by plotting the effect sizes for each fixed-dose level of TAAR1 agonist compared to placebo. However, we did not conduct any formal subgroup test or dose-response meta-analysis due to the limited number of studies.
Moreover, it should be noted that we presented the effect sizes in each specific subgroup of participants for all outcomes, but we did not perform a formal subgroup test
Figure 66 Forest plot presenting the effects of ulotaront and ralmitaront compared to placebo on overall symptoms in acute schizophrenia at 4-6 weeks separately.
Figure 67 Effect sizes for each dose level of ulotaront and ralmitaront compared to placebo in improving overall symptoms of acute schizophrenia at 4-6 weeks are presented separately. The findings of each study are presented separately, and the effect sizes were corrected for using the same control condition in each study. It should be noted that Koblan 2020 was a two-arm flexible dose study, and its effect size is placed in the middle of the range of the administered dose (50mg/d to 75mg/d)
In the fixed-dosing studies, higher doses (i.e., ulotaront 100mg/d and ralmitaront 100mg/d) may be associated with more improvement compared to smaller doses. However, the effect sizes at these high doses still appear to be small, with a standardized mean difference (SMD) of approximately 0.2. In the flexible dosing study by Koblan et al. 2020, which utilized doses of ulotaront up to 75mg/d, small-to-medium effect sizes were observed. Importantly, the available data are limited. Therefore, the findings are inconclusive.
We did not conduct the following sensitivity analyses for the primary outcome due to the limited data: 1) Restricting the analysis to studies with low risk of bias, since there were 4 studies with low risk of bias in acute schizophrenia, and 1 study with high risk of bias in Parkinson’s disease psychosis (1 study with high risk of bias). 2) Excluding imputed data, since no imputed data were used in the analysis of the primary outcome.” There were no imputed data in the analysis of the primary outcome.
Due to the limited number of studies, we also presented a fixed-effects model for all outcomes in addition to the random-effects model to assess the robustness of the findings. The findings were robust in the majority of cases. For the primary outcome in the meta-analysis of 4 studies in acute schizophrenia, the point estimate of the effect sizes did not differ between random- and fixed-effects (SMD=0.15 and 0.13, respectively), but the 95% CI in the fixed-effects model was narrower, excluding the null effect (95% CI: -0.05, 0.34, and 0.02, 0.05, respectively). Nonetheless, the interpretation of the findings that TAAR1 agonists have little to no effect compared to placebo in improving overall symptoms does not change
Reporting bias was evaluated using the ROB-ME tool, taking into account the usable data from the eligible studies identified in the search, the comprehensiveness of the search, and potential patterns of missingness and small-study effects. We followed the algorithm to assign a low or high risk of reporting bias, or to express some concerns, by answering signaling questions related to the domains mentioned above.
There were insufficient data for the primary outcome but also other outcomes (i.e., fewer than 10 studies) to examine small-study effects with funnel plots. Thus, we cannot examine any particular pattern of missing evidence.
We conducted a comprehensive search for both published and unpublished studies in multiple electronic databases, supplemented by manual searches of the reference lists of included studies and previous reviews. Screening was carried out by at least two independent reviewers. All studies identified in the search were conducted by the pharmaceutical industry. Although we contacted them, we have not received additional data for the first iteration. Considering that all eligible studies are experimental and were conducted recently, it is expected that most, if not all, have been registered, thus facilitating their detection during searches in clinical trial registries. Nonetheless, it’s possible that small phase I studies focusing on pharmacokinetics may not have been registered and could therefore have been overlooked. Consequently, we do not anticipate that our search has missed any major or significant studies (ROB-ME-3.1: No, ROB-ME-3.2: PY, ROB-ME-3.3:PY).
The results matrix of the eligible studies found in the search for the primary outcome can be found below in Table 2.
| Name | Diagnosis | Sample size | Data availability |
|---|---|---|---|
| Isaacson (2023) | Parksinon disease psychosis | 39 | ✓ |
| Koblan (2020) | Schizophrenia spectrum | 245 | ✓ |
| NCT04072354 (2019) | Schizophrenia spectrum | 463 | ✓ (adult) / ?(adolescent) |
| NCT04092686 (2019) | Schizophrenia spectrum | 462 | ✓ |
| NCT04512066 (2020) | Schizophrenia spectrum | 287 | ✓ |
| NCT04825860 (2021) | Schizophrenia spectrum | 480 | ~ |
Table 2 Results matrix for the primary outcome. ✓: A study result is available for inclusion in the meta-analysis.; ~:No study result is available for inclusion in the meta-analysis, for a reason unrelated to the P value, magnitude or direction of the result.; ?: Unclear whether an eligible study result was generated. *NCT04072354 included two parts, i.e., adults (sample size 435) and adolescents (sample size unclear but it was probably 28; planned 90). It should be noted that all of the other studies included adult populations. **NCT04825860 is an ongoing trial.
Data were available for all eligible studies concerning the primary outcome, i.e., answers to the ROB-ME signalling question 4.1: no, ROB-ME-4.3: “yes” for adolescents, ROB-ME-4.4: “no”, thus leading to low risk of reporting bias - considering also the comprehensiveness of the search.
The results matrix in Table 2 could also apply to the secondary efficacy outcomes in acute psychosis, although some studies did not have usable data for these outcomes. Specifically, the two phase III trials, NCT04092686 and NCT04072354, did not report effects on symptom domains. Consequently, these analyses would be prone to bias due to missing evidence (ROB-ME-4.1: Yes, ROB-ME-4.2: Yes, thus leading to high risk of reo ).
Additionally, we identified the total number of eligible and completed studies, with or without usable data, that could contribute to dropout and safety data for each comparison (as shown in Table 1): 1) There were 12 studies with 626 participants for the comparison of TAAR1 agonists versus placebo over a period of 1 day to 2 weeks. 2) There were 2 studies with 100 participants for the comparison of TAAR1 agonists versus placebo over the same duration. 3) For the comparison of TAAR1 agonists versus placebo over 3-13 weeks (as detailed in Table 2), there were 6 studies involving 1550 participants, including also 1 study (NCT03669640) focusing predominantly on negative symptoms. 4) Finally, it should be noted that one study (NCT04115319) with 475 participants could contribute to the comparison of TAAR1 agonists versus other antipsychotics for periods exceeding 13 weeks. However, no usable data for this analysis were available from any other study.
The reasons for the missingness of data for these outcomes can be unclear, either due to them not being measured or not reported because of unfavorable findings. As a general rule, we employed the approach responding to ROB-ME-4.3: ‘yes’, ROB-ME-4.3: ‘yes’, ROB-ME-4.2: ‘yes’ if less than 50% of the studies or participants had usable data (balancing the fact that additional data in this small number of studies and participants could impact the findings, but the missingness may not be related to the findings of these outcomes but rather to other factors), and ‘no information’ otherwise. Thus, if there were usable data for fewer than 50% of the eligible studies or participants, we judged there to be a high risk of reporting bias. Otherwise, considering ROB-ME-4.5: ‘no’ and ROB-ME-4.7 and ROBM-4.8: ‘no’ (due to insufficient data to identify patterns of missing evidence and to conduct sensitivity analysis), we assigned some concerns. We also considered potential narrative descriptions of these outcomes or other factors in order to optimize the judgments, and we mention them in the summary of evidence tables below.
The primary outcome was efficacy in reducing overall symptoms in acutely ill patients with psychosis, i.e., available data for adults with Parkinson disease psychosis and schizophrenia spectrum (analyzed separately). There were available data for two comparisons, i.e., TAAR1 agonists (ulotaront or ralmitaront) vs. placebo, and TAAR1 agonist (ralmitaront) vs. antipsychotics (risperidone). The summary of the evidence on the primary outcome for the above mentioned populations and comparisons are reported below.
| Source of evidence | Summary of the association | Bias due to study limitations | Bias due to reporting bias | Bias due to indirectedness | Bias due to other reasons |
| TAAR1 agonist. vs placebo in adults with Parkinson disease psychosis | n=1, k=37, SMD= -0.28, 95%CI: -0.95, 0.38 | 100% of the studies had an overall high risk of bias (due to missing outcome data, unclear direction and impact on the findings) | Low risk of reporting bias | Data available only for ulotaront. No other clear indication of indirectness in terms of population, interventions and outcomes | No clear indication of other biases |
| TAAR1 agonist. vs placebo in adults with schizophrenia spectrum disorder | n=4, k=1291, SMD=0.15, 95%CI: -0.05, 0.34, tau2=0.024 | All studies had an overall low risk of bias (some concerns due to missing outcome data, unclear direction and impact on the findings - potentially minimal) | Low risk of reporting bias | Data available only for ulotaront (3 studies) and ralmitaront (1 study).No other clear indication of indirectness in terms of population, interventions and outcomes | The phase III ulotaront trials conducted during COVID-19, which could be associated with factors assocaited with increased placebo effects and smaller effect sizes. No clear dose-effects. |
| TAAR1 agonist. vs other antipsychotics in adults with schizophrenia spectrum disorder | n=1, k=156, SMD=-0.53, 95%CI: -0.86, -0.20 | One study with an overall low risk of bias (some concerns due to missing outcome data, unclear direction and impact on the findings - potentially minimal) | Low risk of reporting bias | Data available only for ralmitaront (no data for ulotaront) and risperidone (no data for other antipsychotics). No other clear indication of indirectness in terms of population and outcomes | No clear indication of other biases |
k: number of studies, n: number of participants, I2: I-squared, SMD>0 indicates a favourable effect for the TAAR1 agonist. It should be noted that there is low confidence evidence that studies with high risk of bias in misisng outocme data may underestimate the effects (PMID: 37939743).
TAAR1 agonists may have little to no effect compared to placebo on overall symptoms in acutely ill adults with schizophrenia spectrum disorder (SMD=0.15, 95%CI: -0.05, 0.34). Specifically, the confidence in the evidence was low due to some concerns in imprecision (95%CI crossed line of no differences and 0.1) and some concerns in heterogeneity (although could not be well estimated due to the small number of studies).
TAAR1 agonists may be less efficacious with a medium effect size compared to other antipsychotics in improving overall symptoms in acutely ill adults with schizophrenia spectrum disorder (SMD=-0.53, 95%CI: -0.86, -0.20). The confidence in the evidence was low due to some concerns in imprecision (although 95%CI did not cross the range of equivalence, the sample size was small <800 participants) and some concerns in indirectness (no data ulotaront and other antipsychotics).
TAAR1 agonists may have little to no effect compared to placebo on overall symptoms in acutely ill adults with Parkinson disease psychosis (SMD=-0.28, 95%CI: -0.95, 0.38) and the evidence is very uncertain. Specifically, the confidence in the evidence was very low due to major concerns in imprecision (95%CI crossed beyond SMD -0.1 and 0.1, and the sample size was very small <800 participants), and some concerns in the risk of bias (study with a high risk of bias).